Salt sensitivity is a common trait in patients with essential hypertension, and is more prevalent among African Americans, obese and elderly patients, and patients with renal insufficiency or diabetes. These subpopulations are particularly susceptible to detrimental effects of salt on glomerular hemodynamics and renal tissue damage that are independent of or in addition to elevated blood pressure. Although the possible role of genes encoding for several neurohormonal factors in the pathogenesis of increased salt sensitivity has been studied extensively both in humans and experimental animal models, the majority of these genetic studies has thus far been inconclusive. These drawbacks suggest either that the models applied have been inadequate to detect the defects, or that the "salt pathway" is so complex that there are no single defects accounting for a large fraction of the variation in blood pressure or organ dysfunction. Evidence accumulated in our laboratory supports the unique hypothesis that the transient receptor potential vanilloid 1 (TRPV1) channels expressed in renal specific afferent nerves are key molecules in sensing salt induced elevation of endovanilloid concentrations in the kidney (specific aim 1). Activation of TRPV1 by novel endovanilloids counteracts pro-hypertensive neurohormonal systems by inhibiting sympathetic nerve activity (specific aim 2), renal glomerular endothelin (ET1) production, and ET1-induced oxidative stress (specific aim 3), resulting in natriuresis, lowering of blood pressure, and organ protection. Impairment of TRPV1 leads to salt sensitivity and renal tissue injury in the face of salt load (specific aim 4). These studies represent an original effort to define dynamic interactions between the newly discovered endovanilloid/TRPV1 system and the powerful pro-hypertensive neurohormonal systems, and to understand how they may synergistically modulate salt/water homeostasis and protect the kidney from injury. The results of proposed studies in the present application may have important implications both for designing future epidemiological and genomic/genetic studies targeting on various components of the endovanilloid/TRPV1 system, and for developing novel therapeutic agents that act selectively on this system for treatment of hypertension and its related end organ damage. PUBLIC HEALTH RELEVANCE: This competitive renewal tests the hypothesis that the newly discovered endovanilloid/TRPV1 system counteracts the powerful pro-hypertensive neurohormonal systems and protects against renal functional and tissue damage in the face of salt load. Impairment of the system leads to increased salt sensitivity and salt-induced tissue injury. The data may have important implications for the design of epidemiological and genomic/genetic studies targeting on various components of this system and for the development of novel therapeutic agents that act selectively for treatment of salt sensitive hypertension and its related end organ damage.